TY - JOUR T1 - Coupling of β2-Adrenoceptors to XLα<sub>s</sub> and Gα<sub>s</sub>: A New Insight into Ligand-Induced G Protein Activation JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 350 LP - 359 DO - 10.1124/jpet.108.149989 VL - 329 IS - 1 AU - A. I. Kaya AU - Ö. Uǧur AU - S. S. Öner AU - M. Bastepe AU - H. O. Onaran Y1 - 2009/04/01 UR - http://jpet.aspetjournals.org/content/329/1/350.abstract N2 - Gαs and extra-large Gαs (XLαs) can both transduce receptor activation into intracellular cAMP generation. It is unknown, however, whether these two GNAS-locus products display distinct properties with respect to receptor coupling. Here, we show that XLαs couples to the β2-adrenoceptor more efficiently than Gαs. In transfected human embryonic kidney 293 cells and mouse embryonic fibroblasts null for both Gαs and XLαs (2B2 cells), basal cAMP accumulation mediated by XLαs was higher than that mediated by Gαs. Inverse agonist treatment reduced Gαs-mediated basal activity, whereas its effect was markedly blunted on XLαs-mediated basal activity. Rank order of ligand efficacies regarding cAMP accumulation was the same when the receptor was coupled to XLαs or Gαs. However, ligand-induced and XLαs-mediated cAMP generation was higher than that mediated by Gαs. The relatively high efficiency of XLαs-mediated cAMP generation was conditional, disappearing with increased level of receptor expression or increased efficacy of ligand. Full-agonist responses in XLαs- and Gαs-expressing cells were comparable even at low receptor levels, whereas partial agonist responses became comparable only when the receptor expression was increased (&gt;3 pmol/mg). Radioligand binding studies showed that the high-affinity component in agonist binding to β2-adrenoceptor was more pronounced in cells expressing XLαs than those expressing Gαs. We discuss these findings in the framework of current receptor-G protein activation models and offer an extended ternary complex model that can fully explain our observations. The American Society for Pharmacology and Experimental Therapeutics ER -